Chronic systemic inflammation is associated with immune dysfunction and morbidities in the elderly, treated HIV infection, and HCV infection. We propose that circulating inflammatory proteins drive immune exhaustion and senescence and contribute to the immune dysfunction seen in these patient groups. Nearly 4 million Americans are infected with Hepatitis C Virus (HCV) and the mean age of US veterans infected with HCV is nearing 65 years. Although the new IFN-free direct-acting antiviral therapy is highly effective at clearing virus from patients, the patients are left with the consequences of decades of infection and liver damage, and it is still unclear how long soluble mediators of inflammation persist, and how long immune dysfunction and associated morbidity lasts. Similarly, even HIV-infected patients that have successfully controlled viral replication with ART for decades have increased mortality and morbidity and persistent inflammation. The VA is the largest single provider of HIV care in the US. Understanding what causes the continued morbidity in these veteran patient populations is critical. The elderly, HCV and HIV-infected patients all have chronic immune inflammation and these three patient groups share many of the same comorbidities including cardiovascular disease, cancer, and liver disease. The project design of this CDA-2 application is based on the understanding that patients with chronic viral infections and elderly patients show chronic elevated plasma levels of IL-6, and our more recent data demonstrating elevated levels of IL-1? in lymph nodes of HIV-infected patients. The central goals of this study are to determine the underlying mechanisms of IL-6 and IL-1? that contribute to the development of immune exhaustion and senescence and to examine the potential therapeutic role of temporarily blocking IL-6 and IL-1? during chronic infection to improve immune function and recovery of exhausted or senescent T cells. The hypothesis that chronic elevated levels of IL-6 and IL-1? during aging, HCV infection and HIV infection contribute to immune senescence and exhaustion and resulting immune dysfunction will be tested in 3 specific Aims. Aim 1 will determine the phenotype and function of T cells that have been exposed to IL-1? or IL-6 in vitro by sorting the cells positive for exhaustion or senescent markers (PD-1, CD57, Tim-3, KLRG1, Lag3) and examining their functional abilities to determine if inflammatory cytokines alone can drive senescence, independent of antigen exposure. Aim 2A will examine the expression levels of exhaustion and senescent markers and the intracellular production of cytokines associated with the senescence-associated secretory phenotype (SASP) in lymphocytess from HCV-infected, treated HIV-infected, and elderly patients by flow cytometry. Aim 2B will examine the recovery and normalization of immune function, longitudinally, in HIV-infected patients after initiation of ART and in HCV-infected patients after initiation of IFN-free direct-acting antiviral therapy. In Aim 3 we will use a mouse model of chronic viral infection (LCMV) to determine the effect of late blockade of IL-6 and IL-1? on the development of exhausted and senescent T cells, and the recovery of T cell function and proliferative ability. The candidate's long term goals are to understand the effects of chronic inflammation on health, the mechanisms by which the immune system maintains homeostasis, and how inflammation disrupts the ability of the immune system to reestablish homeostasis after infection and during aging. This focus supports a growing need nationwide to advance our understanding and develop therapeutic strategies in the aging veteran population with and without chronic viral infection. The candidate's career goals are to use this Career Development Award to successfully transition to an independent investigator at the Louis Stokes Cleveland VAMC, and to establish a productive, thriving, national leading research program in the VA system.